Study
TCRS
(1995)
FACET
(1997)
Subjects
Newborn US children (n=826) at a single
center (Tucson, AZ).
UK/European adults 18-70 yo (n=852)
with asthma ≥ 6 months and treated with
ICS ≥ 3 months, with FEV1 ≥ 50% and ≥
15% improvement in FEV1 after SABA.
Primary interventions
 Prospective study with assessments during
infancy and at 6 yo.
o
Studies done during infancy: cord
serum IgE, PFT at <6 mo (before
1st respiratory infection, by chest
compression technique), IgE at 9
mo, questionnaire at 1 yo, and
seen in study clinic for each
respiratory tract illness until 3 yo.
o
Studies at 6 yo: IgE, SPT, PFT,
questionnaire.

Excluded if they had 3 or more courses of
oral steroids during past 6 months,
hospitalized for asthma in past 6 months,
or needed high dose ICS
(beclomethasone 2000 ug MDI qd,
budesonide 1600 ug qd, budesonide 800
ug DPI qd, fluticasone 800 ug MDI qd)
Prior to study, all patients placed on
budesonide 800 ug DPI BID with SABA PRN
x 4 weeks (run in period). If asthma stable
after run-in, patients were randomized
into the following 4 groups for 1 year:
o Budesonide 100 ug BID with
formoterol 12 ug DPI BID (n=210)
o Budesonide 100 ug DPI BID with
placebo (n=213)
o Budesonide 400 ug DPI BID with
formoterol 12 ug DPI BID (n=215)
o Budesonide 400 ug DPI BID with
placebo (n=214)
Results (all significant with P<0.05)
 Subjects categorized by wheezing history:
o
Never wheezed = 51.5%
o
Transient early wheezing (wheeze at <3 yo but not at 6 yo) = 19.9%

Associated with maternal smoking.

Decreased lung function at infancy and 6 yo.
o
Late-onset wheezing (wheeze at 6 yo only) = 15%

Associated with maternal asthma, male, rhinitis in the first year of life, atopy
on SPT at 6 yo.

Normal lung function at infancy and 6 yo.

22.5% given asthma dx at 6 yo.
o
Persistent wheezing (wheeze at <3 yo and at 6 yo) = 13.7%

Associated with maternal asthma, maternal smoking, rhinitis apart from
colds, eczema during the first year of life, male, Hispanic, elevated IgE at 9
mo and 6 yo, atopy on SPT at 6 yo.

Normal lung function at infancy, decreased function at 6 yo.

46% given asthma dx at 6 yo.

No association with cord blood IgE

Outcomes:
o
o
o
o
CAMP
(2000)
US children 5-12 yo (n=1024) with mildmoderate asthma (defined by the
presence of sx ≥2X/wk, or by use of a
SABA ≥2X/wk, or the use of daily
medication for asthma), and PC20 ≤ 12.5
mg/ml.

Budesonide DPI 200 μg BID (n=311) vs.
nedocromil 8 mg BID (n=312) vs. placebo,
for 4.3 years (average).

Allowed albuterol prn, oral prednisone for
exacerbations, addition of
beclomethasone dip. 168 μg BID for poor
control (with replacement or adding more
meds allowed if still poorly controlled),
tapering off meds for remission.

Placebo grouped received
beclomethasone or other asthma
controller meds for 20% of study days.
Rate of severe asthma exacerbations per year (defined as requiring PO steroids or
decrease in PEF >30% for 2 consecutive days)

Low dose ICS (0.91) > Low dose ICS + LABA (0.67) > High dose ICS (0.46) >
High dose ICS + LABA (0.34)

Percent of patients without severe exacerbation: High dose ICS + LABA
(80.8%) > High dose ICS (71.8%) = Low dose ICS + LABA (70.3%) > Low dose
ICS (61.4%)
Rate of mild asthma exacerbations per year (defined as decrease in PEF >20% for a day,
use of >3 inhalations of SABA in a day, or awakening at night due to asthma)

Low dose ICS (35) > Low dose ICS + LABA (21.3) = High dose ICS (22.3) > High
dose ICS + LABA (13.4)
Episode-free days, percentage of year (defined as no SABA use, symptom score 0, PEF
at least 80% of baseline)

High dose ICS + LABA (54.8) > Low dose ICS + LABA (51.1) > High dose ICS
(45.7) > Low dose ICS (41.7)
FEV1 (% of predicted), mean over 1 year

High dose ICS + LABA > Low dose ICS + LABA > High dose ICS > Low dose ICS

No difference between budesonide and placebo in:
o
FEV1
o
likelihood to discontinue study meds
o
bone density, fractures, cataract
o
depression questionnaire

Budesonide group with:
o
decreased AHR (via methacholine challenge)
o
shorter height and height percentile (~1 cm and 4%)
o
lower daily sx score, more episode-free days
o
less albuterol use, less additional controller med use
o
less prednisone use
o
increased likelihood to taper study meds
o
fewer urgent care visits, fewer hospitalizations vs. placebo
SMART
(2006)

US subjects ≥12 yo with asthma (as
judged by study physician) and
currently receiving prescription
asthma medication.


Excluded if ever used LABA,
pregnancy, significant systemic
disease, or current use of betablocker.


Multicenter (over 6000 sites).
Recruitment in 2 phases (~3 years
each): phase 1 via media advertising,
phase 2 directly by study
investigators.

PACT
(2007)
Salmeterol 42 μg MDI BID added to
current medications (n=13,176) vs.
placebo (n=13,179) added to current
medications, for ~6.5 months (28 weeks).

GlaxoSmithKline terminated the study early due to preliminary findings in AAs and difficulties in
enrollment (but predefined criteria for study termination were not met at the interim analysis).

Primary endpoint: occurrence of respiratory-related (includes asthma-related) deaths or respiratoryrelated life-threatening experiences, defined as intubation and mechanical ventilation.
o
No difference between salmeterol and placebo for total population.
o
AA/salmeterol subgroup with statistically significant relative risk (4) for primary
endpoint vs. AA/placebo
o
No difference between phase 1 and phase 2 for total population.
o
AA/salmeterol/no ICS subgroup with statistically significant RR (5.6) for primary
endpoint vs. AA/placebo/ICS

Secondary endpoints:
o
Total pop/salmeterol with statistically significant RR for the following: combined
asthma-related death or life-threatening experience (1.7), respiratory-related death
(2.1), asthma-related death (4.3)
o
Caucasian subgroup with no difference between salmeterol and placebo.
o
AA/salmeterol subgroup with statistically significant RR for the following: combined
asthma-related death or life threatening experience (4.9), combined all-cause death or
life-threatening experience (2.1).
o
By phase of trial:

Total pop/salmeterol with statistically significant RR (1.8) for combined
asthma-related deaths or life-threatening experiences during phase 1; No
difference in secondary endpoints during phase 2.
o
By baseline ICS use:

Total pop/salmeterol/no ICS with statistically significant RR (2.39) for
combined asthma-related death or life-threatening experience.

Caucasian subgroup with no difference between ICS and no ICS.

AA/salmeterol/no ICS subgroup with statistically significant RR (10.4) for
combined asthma-related death or life-threatening experience.

Primary outcome: percent of asthma control days during study (defined as a day w/o albuterol, oral
steroids, additional controller medication, day/night sx, unscheduled PCP/ER visits, hospitalizations,
school absence due to asthma)
o
Fluticasone (64.2 %) = combination (59.6 %) > montelukast (52.5 %)

Secondary outcomes (change vs. baseline):
o
Change in FEV1: Fluticasone (+6.3 %) = combination (+3.6 %) > montelukast (-0.58 %)
o
Decrease in eNO: Fluticasone (-59.1 %) > combination (-22.9 %) > montelukast (-18.9 %)
o
AHR via methacholine challenge: Fluticasone > combination = montelukast
o
Proportion of subjects not requiring oral steroids during study: Fluticasone (~60%) =
combination (~48%) > montelukast (~42%)
o
Growth: no difference between treatments
Contacted by phone Q4 weeks to assess
study endpoints.
Baseline ICS use by 47% overall (49%
in Caucasians and 38% in African
Americans). Data for asthma history
and current nocturnal symptoms
indicate greater disease severity at
baseline in the AA subgroup vs.
Caucasian.
US children 6-13 yo (n=285) with mildmoderate persistent asthma (via
reported sx, SABA use, or peak flow <80%
calculated), FEV1 ≥ 80%, PC20 ≤ 12.5
mg/ml.
Excluded if history of life threatening
asthma, >4 courses oral steroids or 2
hospitalizations in past year.

Fluticasone 100 μg DPI BID (n=86) vs.
“combination” fluticasone/salmeterol
100/50 μg DPI QAM + salmeterol 50 μg DPI
QHS (n=81) vs. montelukast 5 mg PO QHS
(n=83), for 48 weeks (11 months).
LOCSS
(2007)
US patients ≥6 yo (n=500) with asthma
was acceptably controlled after 4 to 6
weeks of open-label treatment with
fluticasone propionate (Flovent Diskus,
GlaxoSmithKline)

Inclusion criteria for enrollment in the
run-in period: age ≥6 yo, and FEV1≥60%
predicted before SABA, and ≥12%
improvement in FEV1 post-SABA, or
methacholine PC20 ≤8 mg.
6 week run-in period with fluticasone 100
μg DPI BID (run-in period). If asthma
stable, randomized to following groups:
continue fluticasone 100 μg DPI BID
(n=169), fluticasone 100 μg + salmeterol
50 μg DPI QHS (n=165), or montelukast 510 mg PO QHS (n=166) for 16 weeks.

Primary outcome:
o
Time to treatment failure, defined as: ER/hospital vist, need for systemic corticosteroids
or open-label ICS use, fall in pre-SABA FEV1 to more than 20% below baseline value;
decrease in AM PEFR >35% below baseline value on 2 consecutive days; use of ≥10
puffs/day of SABA for 2 consecutive days (excluding exercise premed); refusal of the
patient to continue because of lack of satisfaction with treatment; or judgment by a
physician that the patient should stop treatment for reasons of safety.

fluticasone (20.2%) = fluticasone + salmeterol (20.4%) > montelukast (30.3%)

Secondary outcomes:
o
FEV1 %predicted (pre-SABA):

fluticasone + salmeterol (91.8%) = fluticasone (91.1%) > montelukast (88.8%)
o
Morning PEFR %predicted:

fluticasone + salmeterol (99%) > fluticasone (96.2%) = montelukast (94.7%)
o
Asthma symptom free days:

fluticasone (85.8%) = fluticasone + salmeterol (82.7%) = montelukast (78.7%)
o
Days with use of SABA

fluticasone (18.2%) = fluticasone + salmeterol (17.1%) = montelukast (22.9%)

Primary outcome:
o
Response to each of the 3 step-up therapies was judged on the basis of:

Total amount oral steroids required

Asthma control days (during latter 12 weeks of each 16 week period). ACD
defined as day with w/o albuterol, day/night sx, unscheduled visit to health
care provider, or peak flow <80% of best)

Change in FEV1

A treatment considered to be better if needed at least 180 mg less oral
steroids; if not, better if more asthma control days; if not, better if FEV1
improved at least 5%. If no difference in any parameter, treatments
considered to be same.
o
98% of patients had a differential response, with most responding to LABA step-up
best. Probability of best response: add LABA > increase ICS = add LTRA.
o
Although LABA step-up most likely to provide the best response overall, some children
had a best response to increased ICS or LTRA step-up.

Analysis of predictors of differential response:
o
Response affected by:

Asthma control test >19, more likely to have best response to LABA.

Race - Hispanic and whites most likely to have a best response to LABA, least
to ICS. AA patients equally likely to have a best response to LABA or ICS and
least to LTRA.

Eczema status – without eczema more likely to have best response to LABA.
o
Response not affected by: AHR (PC20 >1.5 vs <1.5 mg/mL), FeNO (>10 vs <10 ppb), 2
receptor genotype (Arg/Arg vs Arg/Gly vs Gly/Gly), age, sex, sensitization to perennial
allergens, baseline FEV1 (>90% vs <90%), bronchodilator reversibility (>10% vs <10%
FEV1), previous use or nonuse of a controller med, baseline number of asthma control
days, and number of recent asthma exacerbations (0 vs ≥1).
Inclusion criteria after the run-in period:
adequate adherence, a pre-SABA FEV1 ≥
80% predicted, Asthma Control
Questionnaire score of <1.5 (0-6 scale,
lower is better); <16 puffs of SABA per
week during final 2 weeks of the run-in
period (excluding exercise
premedication); no hospitalization,
urgent medical care (for asthma), oral
corticosteroid use, or use of additional
asthma medication during the run-in
period; and an absence of febrile illness
within the previous 24 hours.
BADGER
(2010)
US children/teens 6-17 yo (n=165) with
mild-moderate asthma (as defined by
NAEPP), FEV1 ≥ 60%, and FEV1 increase ≥
12% after SABA or PC20 ≤ 12.5 mg/ml. 28 weeks prior to the treatment period,
their asthma was poorly controlled on
fluticasone 100 μg DPI BID.

48 week / 3 period (16 weeks each)
crossover trial. During each 16 week
period, subjects received the following
step-up therapies: increase fluticasone to
250 μg DPI BID, or switch to
fluticasone/salmeterol 100/50 μg DPI BID,
or add montelukast 5-10 mg PO QD (to
fluticasone 100 μg DPI BID).

Allowed albuterol prn, oral prednisone for
exacerbations.
TALC
(2010)
US adults ≥18 yo with asthma confirmed
by bronchodilator reversibility or BHR,
FEV1 ≥ 40% of predicted value, and
nonsmoking status (<10 pack-years).
Enrolled in TALC study if after 4 week
run-in period with beclomethasone 80 μg
HFA MDI BID (all other asthma
medications stopped) patients with FEV1
<70% predicted or if during final 2 weeks
of run-in period they had sx ≥6 days/wk
or used SABA ≥6 days/wk or were
awakened by asthma ≥2 nights/wk.

Prospective 3-way, double-blind, triple
crossover trial (n=210)
 Patients were treated for a 14-wk period
with:
o Beclomethasone 80 μg HFA MDI BID +
tiotropium bromide DPI 18 μg QAM, or
o Beclomethasone 160 μg HFA MDI BID,
or
o Beclomethasone 80 μg HFA MDI BID +
salmeterol 50 μg DPI BID
 Between each 14 wk period, there was a 2
wk washout period with beclomethasone
80 μg HFA MDI BID.

Primary end point: morning PEF
o
tiotropium = salmeterol > double ICS

Secondary end points:
o
Evening PEF

tiotropium > salmeterol > double ICS
o
FEV1 (pre-bronchodilator)

tiotropium > salmeterol = double ICS
o
Asthma-control days (day without symptoms and without use of SABA)

tiotropium = salmeterol > double ICS
o
Asthma exacerbations with PO or IV steroids

double ICS (13) > tiotropium (7) > salmeterol (5)
o
Unscheduled visits for asthma symptoms

double ICS (6) > tiotropium (2) = salmeterol (2)
PEDIATRIC ASTHMA PREVENTION STUDIES
Study
ETAC
(2002)
Subjects
Primary interventions
Conclusions (all significant with P<0.5)
UK children 1-2 yo with active AD for at
least 1 month.

Placebo (n=275) vs. cetirizine 0.25 mg/kg
PO BID (n=274) for 18 month treatment
period, then observation for 18 months.


During the study, choice of treatment for
any conditions manifested by the
children was left to the clinical
investigators/other physicians managing
the children.
Primary end point: time to the onset of asthma (defined as 3 episodes separated by at least 7 days, either
of nocturnal cough with sleep disturbance lasting for at least 3 consecutive nights, wheezing, or a
combination of the 2)
o
No significant difference between placebo and cetirizine groups in probability of
developing asthma after 36 mo. Median time to asthma onset was 27.1 mo for placebo
and 26.5 months for cetirizine.

Analysis of subgroups with elevated grass pollen sIgE (>0.35): elevated
GP/placebo >> others

Analysis of subgroups with elevated dust mite sIgE (>0.35): elevated
DM/placebo > elevated DM/cetirizine > negative DM/cetirizine > negative
DM/placebo

Increased relative risk for developing asthma associated with elevated IgE to
egg (RR 1.4), grass pollen (1.7), DM (1.6), cat dander (1.5), but not milk (1.1)

No difference in eczema improvement between groups. Overall trend toward improvement in eczema
during the course of study in all treatment groups with all patterns of sensitivity.

No significant difference between groups in adverse effects, including EKG (RR, QT).

Development of asthma defined as recurrence of ≥2 out of 3 sx (cough, wheeze, SOB) within the previous
12 mo, with sx that are not triggered only by infections and clinically respond to SABA; not dependent on
the amount of reversibility with SABA.

After 3 years:
o
Excluded if wheezing episodes after 6 mo
old, persistent nocturnal coughing,
chronic pulmonary disease or other
severe disorder likely to interfere with
the study drug or observation of
outcome, regular antihistamine use, oral
cromoglycate use, or systemic steroids in
the previous few weeks before
recruitment.
PAT
(2002)
European children 6-14 yo with AR to
birch and/or grass (with positive SPT ≥3
mm and conjunctival challenge).
Excluded if positive SPT to any allergen
other than grass and/or birch, previous
SCIT treatment, or asthma with need of
daily medication. Study performed at 6
centers.



Subcutaneous IT to birch and/or grass
(maintenance doses: 12 μg Bet v 1, 20 μg
Phl p 5, started before allergy season)
(n=79) vs. no immunotherapy (n=72), for
3 years, then observed for 2 years.
Both groups were allowed to take
symptomatic medication, limited to
loratadine, nasal levocabastine
(antihistamine), ocular sodium
cromoglycate, and nasal budesonide. In
case of asthmatic symptoms, SABA and
ICS could be given.
Methacholine challenge done before
allergy season (baseline), during season,
and each winter for 3 years, and again at
o
o

24% developed asthma in IT group, 44% in controls. 5/6 centers concordant with similar
results.
AHR incrementally decreased each year in IT group, no change in controls.
IT group with improved symptom scores for conjunctivitis after 1st year and rhinitis
after 2nd year vs. control.
After 5 years (3 years IT + 2 years observation):
o
20% with asthma in IT group, 76% in controls (4 subjects lost to follow-up in each
group).
o
No significant difference in AHR between groups. AHR decreased in both groups vs.
baseline.
o
IT group with stable improved symptom scores for conjunctivitis and rhinitis vs. control,
(similar to scores after 1st 3 years).
5 years.
PEAK
(2006)
US children 2.4-3.6 yo (n=285) with
positive asthma predictive index
(frequent wheezing with one of the
following: AD, AR, parent with asthma;
OR 2 of the following: food allergy,
wheezing unrelated to colds,
eosinophilia).

Fluticasone 88 μg BID via
aerochamber/mask (n=143) vs. placebo
(n=142) for 2 years, then observation off
study medication for 1 year.

Allowed albuterol prn, oral prednisolone
for exacerbations, additional controller
meds for poor control (e.g. more
fluiticasone, montelukast).

Additional controller meds used in 13%
(fluticasone) and 21% (montelukast) of
placebo group during 2 year treatment
period.

At end of 2 year treatment period:
o
Fluticasone group with

more symptom free days (93% of treatment period v. 88%)

less prednisolone use for exacerbations

less singulair or additional fluticasone added for poor control

longer time to 2nd course of prednisolone or addition of controller med

decreased airway resistance measured via impulse oscillometry

shorter height (-1.1 cm), with slower growth velocity during 1st year
o

No difference between groups in

albuterol use

time to 1st prednisolone course

unscheduled physician visits and hospitalizations

growth velocity during 2nd year
At end of 3rd year (2 year treatment + 1 year observation period):
o
Fluticasone group with

less additional fluticasone added for poor control (only during 1st 3 months of
observation period)

shorter height (-0.7 cm) at end of 3rd year, with increased “catch-up” growth
velocity during 3rd year
o
No difference between groups in

symptom-free days

albuterol, montelukast, prednisolone use

unscheduled physician visits and hospitalizations

airway resistance via impulse oscillometry
o
Children with a positive response to fluticasone treatment were more likely (OR 2.32) to
have increase in symptoms during observation period.